The present invention relates to xcex2,xcex3-fused lactones, to processes for their preparation and to their use as pharmaceuticals.
The amino acid L-glutamate is the most important excitatory neurotransmitter in the brain. Glutamate receptors can be divided into into two major classes: 1. ionotropic receptors which control the ion channels directly and 2. metabotropic receptors (mGluRs).
Metabotropic glutamate receptors are a heterogeneous class of G-protein-coupled receptors. Pre- and postsynaptically, they modulate the release of glutamate and the sensitivity of the cell to glutamate, respectively. The effects are caused via different second-messenger cascades. This response, in turn, has an effect on the ionotropic glutamate receptors.
Presently, 8 different suptypes of metabotropic glutamate receptors are known, differing in the second-messenger cascade, pharmacology and localization in the brain (review in: Ann. Rev. Pharmacol. Toxicol. 1997, 37, 205).
The present invention relates to xcex2,xcex3-fused lactones of the general formula (I) 
in which
R1 and R2 together represent radicals of the formulae 
xe2x80x83which are optionally substituted up to 3 times by hydroxyl,
R3 represents hydrogen, (C1-C6)-alkyl or represents (C2-C6)-alkenyl
and
R4 represents a radical of the formula xe2x80x94CH2xe2x80x94R5,
in which
R5 represents aryl having 6 to 10 carbon atoms or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to polysubstituted by identical or different substituents from the group consisting of halogen and (C1-C6)-alkyl,
or
R3 represents (C2-C6)-alkenyl
and
R4 represents hydrogen
and their pharmaceutically acceptable salts.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform components in a known manner.
Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiusopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.
In general, aryl represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
In the context of the invention, (C1-C6)-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
In the context of the invention, (C2-C6)-alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 3 to 5 carbon atoms. Examples which may be mentioned are: vinyl, allyl, isopropenyl, but-3-en-1-yl, n-pent-3-en-1-yl and n-hex-3-en-1-yl.
Preference is given to compounds of the general formula (I) according to the invention in which
R1 and R2 together represent radicals of the formulae 
xe2x80x83which are optionally substituted up to 3 times by hydroxyl,
R3 represents hydrogen or represents (C2-C5)-alkenyl
and
R4 represents a radical of the formula xe2x88x92CH2xe2x80x94R5,
in which
R5 represents phenyl, naphthyl or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and (C1-C4)-alkyl,
or
R3 represents (C2-C5)-alkenyl
and
R4 represents hydrogen
and their pharmaceutically acceptable salts.
Particular preference is given to compounds of the general formula (I) according to the invention,
in which
R1 and R2 together represent radicals of the formulae 
which are optionally substituted up to 2 times by hydroxyl,
R3 represents hydrogen or represents (C3-C5)-alkenyl
and
R4 represents a radical of the formula xe2x88x92CH2xe2x80x94R5,
in which
R5 represents phenyl, naphthyl or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and (C1-C3)-alkyl,
or
R3 represents (C3-C5)-alkenyl
and
R4 represents hydrogen
and their salts.
Very particular preference is given to compounds according to the invention of the following structure:
The compounds of the general formula (I) according to the invention can be prepared by
[A] reacting compounds of the general formula (II), 
in which
R1 and R2 are as defined above.
with compounds of the general formula (III)
R4xe2x80x94Axe2x80x83xe2x80x83(III)
in which
R4 is as defined above
and
A represents halogen, preferably bromine,
in inert solvents and in the presence of a base to give the compounds of the general formula (Ia) 
in which
R1, R2 and R4 are as defined above,
and, in the case that R3 does not represent hydrogen, reacting the compounds of the general formula (Ia) with compounds of the general formula (IV)
R3xe2x80x2xe2x80x94Dxe2x80x83xe2x80x83(IV)
in which
R3xe2x80x2 has the meaning of R3 given above. but does not represent hydrogen.
D represents halogen, preferably bromine,
in inert solvents and in the presence of a base,
or
[B] initially reacting compounds of the general formula (II) with compounds of the general formula (IV) as described under [A] to give the compounds of the general formula (Ib) 
in which
R1. R2 and R3xe2x80x2 are as defined above,
and in a second step with compounds of the general formula (III).
The processes according to the invention can be illustrated in an exemplary manner by the formula scheme below: 
Suitable solvents are all inert solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. Particular preference is given to tetrahydrofuran.
Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or amides, such as sodium amide, lithium bis-(trimethylsilyl)amide, lithium diisopropylamide, or organometallic compounds, such as butyllithium or phenyllithium. Preference is given to lithium diisopropylamide and lithium bis-(trimethylsilyl)amide.
Here, the base is employed in an amount of from 1 to 5, preferably from 1 to 2, mol, based on 1 mol of the compounds of the general formulae (III) and (IV).
The reaction is generally carried out in a temperature range of from xe2x88x9278xc2x0 C. to reflux temperature, preferably from xe2x88x9278xc2x0 C. to +20xc2x0 C.
The reaction can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
The compounds of the general formula (I) according to the invention are suitable for use as medicaments in the treatment of humans and animals.
The compounds of the general formula (I) according to the invention are suitable for modulating metabotropic glutamate receptors and therefore influence the glutamatergic neurotransmitter system.
For the purpose of the invention, a modulator of the metabotropic glutamate receptor is an agonist or antagonist of this receptor.
The compounds according to the invention are particularly suitable as modulators of the metabotropic glutamate receptor of subtype 1, very particularly as antagonists of this receptor subtype.
Owing to their pharmacological properties, the compounds according to the invention can be used, on their own or in combination with other pharmaceuticals, for the treatment and/or prevention of neuronal damage or disorders associated with a decompensation of the physiological or with pathophysiological conditions of the glutamatergic system in the central and peripheral nervous system.
For the treatment and/or prevention of neuronal damage caused, for example, by ischaemic, thromb- and/or thrombemolic, and haemorrhagic stroke, conditions after direct and indirect injuries in the area of the brain and the skull. Furthermore for the treatment and/or prevention of cerebral ischaemias after all surgical interventions in the brain or peripheral organs or body parts and conditions of pathogenic or allergic nature accompanying or preceding them, which can lead primarily and/or secondarily to neuronal damage.
Likewise, the compounds according to the invention are also suitable for the therapy of primary and/or secondary pathological conditions of the brain, for example during or after cerebral vasospasms, hypoxia and/or anoxia of previously unmentioned origin, pefinatal asphyxia, autoimmune disorders, metabolic and organ disorders which can be accompanied by damage to the brain, and also damage to the brain as a result of primary brain disorders, for example convulsive conditions and atero- and/or arteriosclerotic changes. For the treatment of chronic or psychiatric conditions such as, for example, depression, neurodegenerative disorders, such as, for example, Alzheimer""s, Parkinson""s or Huntington""s disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and/or chronic viral or bacterial infections and multlinfarct dementia.
Moreover, they can be used as pharmaceuticals for the prevention and/or treatment of dementias of different origin, impaired brain performance owing to old age, memory disturbances, spinal injuries, states of pain, states of anxiety of different origin, medicament-related Parkinson""s syndrome, psychoses (such as, for example, schizophrenia), brain oedma, neuronal damage after hypoglycaemia, emesis, nausea, obesity, addiction and withdrawal syndromes, CNS-mediated spasms, sedation and motor disturbances.
Furthermore, the compounds can be used for promoting neuronal regeneration in the post-acute phase of cerebral injuries or chronic disorders of the nervous system.
They are preferably employed as pharmaceuticals for the prevention and/or treatment of cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms (such as, for example, epilepsy).
The modulation of substances at the metabotropic glutamate receptor (direct or indirect effect on the coupling efficiency of the glutamate receptor to G-proteins) can be examined using primary cultures of granular cells from the cerebellum. Electrophysiological measurements on these cell cultures in the xe2x80x9ccell attachedxe2x80x9d mode show that L-type Ca2+-channels in this preparation are activated by mGluR1-glutamate receptors (J. Neurosci. 1995, 15, 135), whereas they are blocked by group II receptors (J. Neurosci. 1994, 14, 7067). By appropriate experimental arrangement, it is possible to monitor the modulatory effect of pharmacological test substances on glutamate receptors. Detailed examination of subtype specificity under controlled conditions can be carried out by injecting the appropriate mGluR subtype DNA into Xenopus oocytes (WO 92/10583).
Using the test models below, it is possible to demonstrate the antiischaemic activity of the compounds in vivo.
Permanent Focal Cerebral Ischaeiia in the Rat (MCA-O)
Under isoflurane anaesthesia, the medium cerebral artery is exposed on one side and the latter and its side branches are irreversibly sealed by means of electrocoagulation. As a result of the intervention the cerebral infarct is formed. During the operation, the body temperature of the animal is kept at 37xc2x0 C. After wound closure and wearing off of the anaesthesia, the animals are again released into their cage. The administration of the substance is carried out according to different time schemes and via different administration routes (i.v. i.p.) after occlusion. The infarct size is determined after 7 days. To do this, the brain is removed, worked up histologically and the infarct volume is determined with the aid of a computer-assisted analysis system.
Subdural Haematona in the Rat (SDH)
Under anaesthesia, the animal""s own blood is injected subdurally on one side. An infarct is formed under the haematoma. Substance administration is carried out according to different time schemes and via different administration routes (i.v. i.p.). The determination of the infarct size is carried out as described in the model of permanent focal ischaemia in the rat (MCA-O).
Using the method described in NeuroReport 1996, 7, 1469-1474, it is possible to test for antiepileptic activity.
The suitability of the compounds according to the invention for treating schizophrenia can be determined by the methods described in Science 1998, 281, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136.
The present invention includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, comprise one or more compounds of the general formulae (I), (Ia) and (Ib) or which consist of one or more active compounds of the formulae (I), (Ia) and (Ib) and processes for producing these preparations.
In these preparations, the active compounds of the formulae (I), (Ia) and (Ib) should be present in a concentration of from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the total mixture.
In addition to the active compounds of the formulae (I), (Ia) and (Ib) the pharmaceutical preparations may also comprise other pharmaceutically active compounds.
The abovementioned pharmaceutical preparations can be prepared in a customary manner by known methods, for example with the auxiliary(s) or excipient(s).
In general, it has proved advantageous to administer the active compound(s) of the formulae (I), (Ia) and (Ib) in total amounts of about 0.01 to about 100 mg/kg, preferably in total amounts of about 1 mg/kg to 50 mg/kg, of body weight per 24 hours, if appropriate in the form of a plurality of individual administrations, to achieve the desired result.
However, if appropriate, it may be advantageous to depart from the amounts mentioned, namely depending on the type and on the body weight of the object treated, on the individual response towards the medicament, the nature and severity of the disorder, the manner of formulation and administration, and the time or interval at which administration takes place.
Mobile Phases for Chromatography
I Dichloromethane/methanol
II Dichloromethane/ethanol
III Cyclohexane/ethyl acetate
IV Cyclohexane/dichloromethane
V Butyl acetate (200), butanol (26), acetic acid (100), phosphate buffer pH=6 (60)
Abbreviations
DME- 1,2-Dimethoxyethane
HMPA- Hexamethylphosphoric triamide
LiHMDS- Lithium bistrimethylsilylamide
LDA- Lithium diisopropylamide
MTBE- Methyl tert-butyl ether
THF Tetrahydrofuran